17-alpha, 21-diol-3, 20 diketo-4, 6-pregnedienes and a process for their production



Uni ed-St tes 17 ALPHA,21 DIOL 3,20 DIKETO 4,6 PREG- NEDIENES AND A PROCESS FOR THEIR PRO- DUCTION Franz Sondheimer and George Rosenkranz', Mexico City,

'. Mexico, assignors to Syntex, S.A., Mexico City, Mexico,

a corporation of Mexicoi 6 Claims. (Cl. 2fi0-'397.47)

The present invention relates tocycIOpentanOphenanthrene compounds and to a method for the preparation thereof. More particularly, the present invention relates to the oxidation of steroid compounds with manganese dioxide. i In our United States patent application Serial No. 364,184, filed June 25, 1953, there is disclosed the oxidation of steroidal A -3,6-dihydroxy compounds with manganese dioxide at room temperature to the corresponding A -3-keto-6-hydroxy compounds andat elevated temperatures to the corresponding A -3,6-diketones respec tively. In the aforementioned.application therieis also disclosed the oxidation of steroidalA -3; hydroxy"compounds with manganese dioxide to form the corresponding A -3-ketones. V p I In United States application Serial No. 344,246, filed March 23, 1953, there is disclosedthe oxidation of steroidal allyl alcohols with' manganese dioxide. y

In accordance with the present invention, we have discovered that manganese dioxide may be utilised for 2. 3,20dione 21-acetate (21-acetate of the G-dehydro derivative of the cortical hormone Reichsteins substance S).

It has been also discovered in accordance with the present invention that oxidation of an allyl alcohol with 5 manganese dioxide (as disclosed in the aforementioned United States application Serial No. 344,246) may be utilized to prepare steroidal A -12-keto compounds from the corresponding A -12-hydroxy compounds and steroidal A -21 aldehydes from the corresponding A -21- alcoliolslf In practicing the invention the steroid to be treated is preferably dissolved in an organic solvent such as chloro" form-and shaken at room temperature with manganese dioxide for a prolonged period for selective oxidation of the hydroxy group. For the reactions with manganese dioxide in the hot the steroid is similarly dissolved and refluxed with manganese dioxide'for several hours.

The following specific examples serve to illustrate but are not intended .to limit the present invention:

Example I A solution of 2 of the diacetate of A -pregnene- 3fl,6fi-diol-20-one prepared in accordance with Journal of Organic Chemistry 16, 192 ,(l951).'iu 100 cc. ,of methanol was treated with 1.5 g. of sodium hydroxide previously dissolved in 10 cc. of water'and the mixture I was refluxed for one hour, poured into water and exthe oxidation of A 3,6-dihydroxy com-pounds loffthe pregnene and androstene series with the production in some instances of novel A -6-hydroxy-3-ketones' of the androstene and pregnene series. Certain of the 6-hydroxy compounds have already been disclosed as of substantial pharmacological interest and others of the G-hydroxy compounds produced in accordance with the present invention may be readily converted as for example to known 6-keto compounds. Since 6B-hydroxy compounds are produced by biochemical means (United States Patent No. 2,602,769) the product-ionof G/B-hy- 'droxy compounds by chemical methods becomes important for comparison therewith and for theproduction of the same 6-keto compounds for comparative purposes. It has further been discovered in accordance with the present invention that A -pregnene-3fl,l7a-diol-20-one .(17a-hydroxy pregnenolone) may be treated with man.- sganese dioxide to give the novel A -p'regnadiem 17a-pl- 3,20-dione (the .6-deh'ydro derivative of the cortical hormone 17-hydroxyprogesterone, easily converted into the cortical hormone by conventional reduction). Similarly, treatment of A -pregnene-3B,17a,21-triol-20-one 21-ace- 'tracted with ether. The ethersolution was washed to neutral and dried over sodium sulphate. Direct crystallization from ether atiorded yield of n -pregnen- 3d,,6fl-diol-20-one having a melting point of 188-192 C., [al l-95 (chloroform).

50.0 mg. of M-pregnene-S18,6,8-diol-20-0ne dissolved in 100 ,cc. of chloroform was shaken for 24 hr. at room temperature with 10 g. of manganese dioxide. The solution was filtered and evaporated to dryness, Crystallization of the residue from acetone-ether yielded 260 mg. of A -pregnen--ol-3,20-d-ionehaving a melting point of l73-174 C. (the analytical sample had 181483" C.), [a l-1G5 (chloroform). The compound has an ultraviolet absorption maximum 'at" X max-.- 238'mp (log e 4.26). The infrared spectrum confirms the presence pf .aqfree hydroxy group-as well as the A -3-keto and ZO-k'eto groups. l v

A solution of 500 '-mg.. of 6,8 hydroxyprogesterone in 1 2. cc; of pyridine and 2.5,cc. of acetic anhydride was heated on the steam bath for 1 hr. and then poured into water, The product. was worked up under the usual conditions and crystallization from ether-hexane gave 100% yield of the acetate of A -pregnen-6B-ol-3,20-

dione having a melting point of 141-143 c., [aim- (ethanol). The compound has an ultraviolet absorption maximum at A max. 236 m (log 5 4.28). The infrared spectrum confirms the presence of an acetyl group as well as the 20-keto and A -3-keto' groups.

The following equation illustrates the processof the v present example: I

I CH:

Example 11 7 00 mg; of At-pregnene-3p,6p dio1-20 one was dis:-

Arro s solved in 80 cc. of chloroform and mixed with 8 g. of manganese'dioxide. The mixture was refluxed under stirring for 6 hrs., filtered and evaporated to dryness. The residue was chromatographed in a column with 30 g. of washed aluminum oxide. The crystalline fractions eluted from the column and which had'sirnilar melting points were combined, thus giving 320 mg. of A -pregheme-3,6,20-trione (6-ketoprogesterone, a known steroid hormone) which after recrystallization from chloroformether had a melting point of 188-190 C., [a] +24 (chloroform); max. 250 Ill/L (log 6 4.19). In contrast with the product obtained in Example No. I, this product does not exhibit the typical infrared band of free hydroxy groups, but it does shown the typical bands of saturated and unsaturated keto groups.

CHaOAo The following equation illustrates the process of the Example III A solution of 13g. of the triacetate of A -pregnene- 3p,6fl,21-triol-20-one prepared in accordance with Journal of Organic Chemistry 16, 192 (1951) in 300 cc. of methanol was mixed under an atmosphere of nitrogen with a solution of 13 g. of "sodium hydroxide in 60 cc. of water after both solutions had been cooled and the mixture was kept under nitrogen for 24 hrs. at room temperature. It was then neutralized with acetic acid, concentrated to a small volume under reduced pressure, poured into water and the precipitate was extracted with chloroform. Crystallization from chloroform-ether gave '8 g. of A -pregnene-3fi,6;3,21-triol-20-one having a melting point of 200-203 C. (the analytical sample had a melting point of 203-206" C.).

A solution of 970 mg. of A -pregnene-3p,6fl,2l-triol- -oue in 2.5 cc. of anhydrous pyridine was cooled .to 10 C. and mixed with 1.2 molar equivalents of acetic anhydride previously cooled to -10 C. The flask was quickly stoppered and then kept for 24 hrs. at a temperature of -10 C., poured into water and extracted with ether. Chromatography followed by one crystallization from acetone afforded 490 mg. of the 21-monoacetate of A -pregnene-3/3,6B,2l-triol- 20-one having a melting point of 190-l92 C. (the analytical sample had 193-195 C.). The infrared spectrum shows the presence of the free hydroxy. groups and the 21-acetoxy and 20-keto groups- 10 g. of manganese dioxide was added to a solution of l g. of the 21-acetate of A -pregnene-3fi,6;3,21-triol-20-one in 100 cc. of chloroform and the mixture was shaken for 24 hrs. at room temperature, filtered and evaporated to dryness. Crystallization from acetone-ether yielded 600 mg. of the 21-acetate of A-preguene-6p,2Ldiol-LZO-dione having a melting point of 198-200 C. The compound has anultravi'olet absorption maximum at 7*. max. 238 my (log a 4.26). The infrared spectrum confirms the presence of free hydroxy-Zl-acetoxy, 20-keto and A -3- keto groups.

300 mg. of 6fl-hydroxy-desoxycorticosterone ZI-acetate was acetylated wth 1 cc. of pyridine and 1.5 cc. of acetic anhydride by the method described in Example No. I. Crystallization from ether-pentane gave 300. mg. of the diacetate of A -pregnene-6/3,21-diol-3,20-dione having a melting point of 128-130 C., [a] +101 (chloroform). The ultraviolet spectrum has an absorption band at 236 mu (log e 4.18).

The following equation illustrates the process of the present example:

CH OAO Example IV In the same way as described in Example II, 1 g. of the 21-acetate of A -pregnene-3/3,6 8,21-triol-20-one in cc. of chloroform was treated with 10 g. of manganese dioxide. Chromatography of the product and recrystallization from acetone-ether yielded 260 mg. of the acetate of A -pregnen-21-ol-3,6,20-trione (acetate of 6- keto-desoxycorticosterone) having a melting point of 137-139 C., ultraviolet absorption maximum at A max. 248 mp. (log 4: 4.05). The infrared spectrum confirms the presence of an acetyl and 20-keto group, as well as the presence of a A -3,6-diketone.

The following equation illustrates the process of the present example:

(IJH OAo omoxc r 7 00 o (on i i Example V i 3 g. of manganese dioxide was added to a suspension of 1 g. of A -androstene 318,6 8-di0l-17-0ne (prepared by saponification of diacetate; Petrow et al., Journal Chem. Soc. 2536' (1949)) in 100 cc. of chloroform and the mixture was shaken for 24 hrs. at room temperature. The solution was filtered and evaporated to dryness. Crystallization from chloroform-ether afforded 600 mg. of A androsten-6fl-ol-3,17-dione having a melting point of 187- 189 C. (the analytical sample had a melting point of 192-194". C.),[a] (chloroform). The compound shows an ultraviolet absorption maximum at lt max. 236 my. (log 6 4.27). The infrared spectrum indicates the presence of a free hydroxy group and 17-keto and ALB-keto groups.

300 mg. of 6fl-hydroxy-androstene-3,17-dione was acetylated with 1 cc. of pyridine and 1.5 cc. of acetic anhydride such as described in Example I. The product was crystallized from chloroform to give mg. of the acetate of A -androsten-6fi-ol-3,l7 dione having a melting point of 190-194 C. (analyticalsample, melting point iultraviolet absorption maximumat-A max. 234 m (log @421). The infrared spectrum confirms the presence 7\ max-238 my (log. 6 4.25). The'infrared spectrum shows the presence of free hydroxyl and A 3-keto groups.

of l'7-keto and A -3-keto groups. 250 mg. of this 6p-hydroxytestosterone was acetylated' The following equation illustrates the process of the 5 by the method described in previous examples. Chromapresent example: tography and crystallization from ether-pentane yielded 120 mg. of the diacetate of A -androstene-6fl,17fl-diol-3- g. of manganese dioxide was added to a suspension one havmg a meltmg pomt of 132433" []D+2.6.. of l g. of M-androstene-Zlfl,6/8-diol-17-one in 100 cc. (chloroformx A 234 (10g? The of chloroform and the mixture was refluxed for 8 hrs. flared spectrum shows thg presence 9 under stirring. The solution was filtered and evaporated as Wen as the groupestenficaflon to dryness and the residue was chromatographed in a produced other conventional esters especially lower fatty column with 50 g. of previously washed l i esters, such as the propionate, or aromatic esters such oxide. The fractions having similar melting points were as the benzofiificombined, thus i i 310 of A -androstene-3,6,17-' The following equation illustrates the process of the trione having a melting point of 220-221 C., [eth l-43 present example:

T98 201" C), ffiarjli -F10 6? (acetone). It shows an- Example VI The following equation illustrates theprocess of the present example:

Example VIII v 13 g. of manganese dioxide was added to a suspension of 1.37 g. of A -androstene-3B,6fi,l7fi-triol in 130 cc. of chloroform and the mixture was refluxed as described in the previous examples. Chromatography and. crystal- 45 lization from acetone-ether produced 500' mg. of A"- androsten-17fl-ol-3,6-dione having a melting point of 2l3-2l5 C., [M -52 (acetone), A max. 250 mu (log 6 4.17). The infrared spectrum reveals the presence 0 o II I l A of a free hydroxy group and shows a band at 1680 cmr characteristic of unsaturated carbonyl groups. The following equation illustrates the process of the present example: 110- o.-. 011 H I 55 a. O v I Example VII A suspension of 2 g. of lithium aluminum hydride in I anhydrous ether was slowly added to a solution of 4 3g g. of the diacetate of VA -androstene-3B,6B-diol-17-one in tetrahydrofuranc. After decomposing the excess of reagent by the addition of acetone, water was added and the precipitate was filtered and washed. Crystallization from chloroform produced 2.36 g. of A -androstene- 55 33,65,17f3-triol having a melting point of 208-212" C., [M -H3" (dioxane). This compound has no selective Example IX 1 g. of 17a-hydroxypregnenolone suspended in 100 cc. of benzene was oxidized with 10 g. of manganese dioxide absorption in the ultraviolet spectrum and the infrared at the refluxing temperature such as described in the spectrum indicates the presence of free hydroxy groups. previous examples. Crystallization from acetone-ether 1 g. of A -andr0stene-3fl,6/3,17B-triol was dissolved in 7 afforded mg. of A -pregnadien-17a-ol-3,20-dione 100 cc. of chloroform and oxidized with manganese dihaving a melting point of 240-242 C., [a] +21 oxide such as described in the previous examples, at room (chloroform), max. 284 mp. (log 6 4.53). The intemperature. Crystallization from chloroform-ether gave frared spectrum shows the presence of a free hydroxy 480 mg. of A -androstene-6B,17fl-diol-3-one having a group as well as a 20-keto and an unsaturated keto group.

melting point of 215-216 C., lal +35 (chloroform), 75 Selective saturation of the 6-7 double bond as described 2,926,181 7 8 in Example X gave the known hormone 17u-hydroxy- 3,20-dione was dissolved in 300cc. of chlorobenzene and progesterone. 20 cc. of the solvent. was distilled in order to remove The following equation illustrates the process of the traces of moisture; Then 8 cc. of carbon tetrachloride present example: with 0.8 cc. of anhydrous pyridine and 1.6 g. of well powdered N-bromosuccinimide was added and the mix- Example X ture was refluxed for 12 minutes with a:photoflood lamp as source of light and heat. The mixture was cooled, washed with water, dried over sodium sulphate and evaporated to dryness at not too high a temperature under reduced pressure. The residue crystallized upon 3 g. of 2l-acetoxy-17a-hydroxy-pregneno1one dissolved in 300 cc. of benzene was oxidized with 30 g. of manganese dioxide under reflux such as described in previous addition of ether. Recrystallization from acetone-ether gave the 21-acetate of 6-bromo-A -pregnene-17a,21-diol- 3,20-one having a melting point which varied between examples. Chromatography and crystallization from 20 chloroform-ether yielded 1 g. of the Z-acetate of A pregnadiene-17a,21-diol-3,20-dione having a melting point 168 and 177 C., [a] +56 (chloroform).

1.2 g. of this 6-bromo derivative was refluxed for 30 of 218-221 C., [a] +104 (chloroform), max. 284 mp. (log 6 4.48). The infrared spectrum indicates the minutes with 15 cc. of distilled collidine the precipitate of collidine hydrobromide was filtered and the solution presence of the 21-acetoxy group, a free hydroxy group and the ZO-keto and unsaturated keto groups.

was diluted with ether, washed with dilute hydrochloric A solution of 1 g. of this 21-acetate of M' -pregnaacid and water, dried over sodium sulphate and evaporated to dryness. Recrystallization of the residue from diene-17a,21-diol-3,20-dione (6-dehydro derivative of Compound S) in 50 cc. of acetic acid and 50 cc. of henacetone-ether afforded the 21-acetate of A -pregnadienel7oc,2I-diOl-3,20-di0ne having a melting point of 221- 223", [d] +102 (chloroform). This compound has an ultraviolet absorption maximum at 284 m (Log 6 4.50). By direct comparison it showed to be identical to the product obtained in accordance with the method of Example X.

The following equation illustrates the process of the present example: CHgOAo CHrOAc CHzOAc to ('10 I ----0H 50H :----OH I l i o 0 o Br Example XII 500 mg. of A -22a-allospirostene-3fl,1ZB-diol dissolved in 50 cc. of chloroform was oxidized with 5 g. of manganese dioxide shaking for 4 hr. at room temperature such as described in previous examples. Crystallization from chloroform-acetone yielded 370 mg. of A -22aallospirosten-3fl-ol-12-one having a melting point of 220- 223 C., [ab-27 (chloroform), 7\ max. 240 m (Log 6 4.20). The infrared spectrum of this compound shows the presence of a free hydroxy group and has a band at 1670 cm. characteristic of an unsaturated keto group.

zene was shaken under an atmosphere of nitrogen for 20 hrs. at room temperature with 2 g. of granulated zinc (30 mesh) and 0.2 g. of ascorbic acid. The zinc was filtered and the solution was evaporated to dryness. The residue was collected with chloroform and the solution was washed with water and again evaporated to dryness. Crystallization from acetone afforded 0.8 g. of the 2l-acetate of M-pregnene-17a,21-diol-3,20-dione (acetate of Reichsteins Compound S) having a melting point of 239-241 C., [a] +116 (acetone).

The following equation illustrates the process of the present example:

CHsOAG $11202) $11101) c0 00 l I :---OH I :--'0H Example XI The following equation illustrates the process of the present example:

3.2 g. of the 21-acetate of A -pregnene-17a,21-diolf 1 5 l U 9. Exampie XIII 500 mg. of A -pregnadiene-BBJl-diol dissolved in 50 cc. of chloroform was oxidized with 5 g. of manganese dioxide shaking for 5 hrs. at room temperature such as described in previous examples. Crystallization from acetone afforded 325 mg. of A -pregnadien- 3,8-ol-21-al having a melting point of 178l80 C., A max. 244 m (Log 6 4.29).

The following equation illustrates the process of the present example:

CH0]; CH0

This application is a division of application Serial No. 406,571, filed January 27, 1954, now Patent No. 2,786,855, granted March 26, 1957.

We claim:

1. A process for the production of a compound selected 10 from the class consisting of n -pregnadiene-flwol- 3,20-dione, A -pregnadiene-17a,2l-diol-3,20-dione and lower fatty acid esters thereof which comprises treating the corresponding A -3-hydroXy-pregnene compound with manganese dioxide.

2. The process of claim 1 wherein the product is A' -pregnadiene-17a-ol-3,20-dione and the starting compound is A -pregnene-3 9,17a-diol-20-one. V

3. The process ofclaim 1 wherein the product is the ZI-acetate of A -pregnadiene-17m21-diol-3,2O-dione and the starting compound is the ZI-acetate of A -pregnene- 3B,17a,21-triol-20-one.

4. A compound selected from the group consisting of A -pregnadiene-17,21-diol-3,20-dione and lower fatty acid esters thereof.

5. The 21-acetate of A -pregnadiene-17a,21-diol-3,20- dione.

6. A -pregnadiene-I7a,21-diol-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS Murray Feb. 23, 1 954 Colton Mar. 27, 1956 

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND SELECTED FROM THE CLASS CONSISTING OF $4,6-PREGNADIENE-17A-OL3,20-DIONE, $4,6-PREGNADIENE-17A,21-DIOL-3,20-DIONE AND LOWER FATTY ACID ESTERS THEREOF WHICH COMPRISES TREATING THE CORRESPONDING $5-3-HYDROXY-PREGNENE COMPOUND WITH MANGANESE DIOXIDE.
 3. THE PROCESS OF CLAIM 1 WHEREIN THE PRODUCT IS THE 21-ACETATE OF $4,6-PREGNADIENE-17A,21-DIOL-3,20-DIONE AND THE STARTING COMPOUND IS THE 21-ACETATE OF $5-PREGNENE3B,17A,21-TRIOL-20-ONE. 